Key points

Introduction

Atopic dermatitis (AD) is a paradigmatic disease that has always challenged the scientific community with regard to its origin and the wide spectrum of the clinical phenotype. The multiple denominations for this disease over the last century underline this lack of consensus with regard overall to the understanding of the origin of the disease. The term AD was coined by Wise and Sulzberger in 1933 and has merely adopted over the time. In the last 2 decades or so, there have been a number of attempts to redefine the disease according to more modern insights based on epidemiologic studies, genetic findings as well as immunologic pathomechanisms underlying the disease.

Without going much into the discussion of whether or not the term AD is the most suitable one for this condition, one should notice that it has been always a tradition in medicine and particularly in dermatology that designations of the diseases usually are based on a composite name typically relying to a symptom on one hand and an adjective for the context of that symptom on the other. Typical examples for this kind of denomination are mycosis fungoides, lichen planus, psoriasis vulgaris, lupus erythematodes or in our particular case, atopic dermatitis . The scientific community nowadays acknowledges the complexity of the clinical phenotype and of the pathophysiologic background of AD. The phenotype may rather correspond with a common set of symptoms that the skin has found in his own language to express the various underlying mechanisms that we just start to understand. The term “skin disease” has recently been proposed for this particular situation.

Introduction

Atopic dermatitis (AD) is a paradigmatic disease that has always challenged the scientific community with regard to its origin and the wide spectrum of the clinical phenotype. The multiple denominations for this disease over the last century underline this lack of consensus with regard overall to the understanding of the origin of the disease. The term AD was coined by Wise and Sulzberger in 1933 and has merely adopted over the time. In the last 2 decades or so, there have been a number of attempts to redefine the disease according to more modern insights based on epidemiologic studies, genetic findings as well as immunologic pathomechanisms underlying the disease.

Without going much into the discussion of whether or not the term AD is the most suitable one for this condition, one should notice that it has been always a tradition in medicine and particularly in dermatology that designations of the diseases usually are based on a composite name typically relying to a symptom on one hand and an adjective for the context of that symptom on the other. Typical examples for this kind of denomination are mycosis fungoides, lichen planus, psoriasis vulgaris, lupus erythematodes or in our particular case, atopic dermatitis . The scientific community nowadays acknowledges the complexity of the clinical phenotype and of the pathophysiologic background of AD. The phenotype may rather correspond with a common set of symptoms that the skin has found in his own language to express the various underlying mechanisms that we just start to understand. The term “skin disease” has recently been proposed for this particular situation.

Is it eczema or dermatitis ?

Interestingly, although physicians mean the same syndromic situation called herein AD, depending on the countries the preferred name can be different and this phenomenon certainly has a significant impact for many different aspects of practical relevance. For example, the term eczema is more commonly used in the UK and in countries of the Commonwealth, whereas atopic eczema and atopic dermatitis are rather used and mixed up in other countries. A particular situation is observed in China, where eczema and atopic dermatitis are considered as 2 different diseases (see below). Sticking to the original meaning of the word eczema , coming from the Greek word εκσειν (eksein), which means “boiling,” this denomination, particularly without the adjective atopic , seems the less suitable because it strongly suggests a disease in an acute situation with vesicles as a major clinical sign. Based on that and with regard to the classical clinical symptoms of this condition, the word eczema would seem the less appropriate for this disease, in particular when the adjective atopic is not combined. Therefore, a new discussion has been started on an global level with the aim to harmonize at least the denomination of the condition because this is expected to have significant relevance for a more global approach in terms of research, education, prevention, and drug development.

How to define atopy ?

Beside the wording eczema or dermatitis , the definition of atopy is probably much more challenging. When facing the particular situation of a special familiar hyperresponsiveness against allergens, Coca and Cooke asked the philologist Edward Perry to find a suitable term. Finally, they agree to the artificial term atopy which is derived from the Greek word ατοποσ (atopos) and means “not in the right place, not in the precise place, unusual, strange.” Since then, this nonmedical term survived overtime and has been accepted to describe this particular kind of syndrome including an involvement of different target organs, such as the skin, lung, nose, and/or eyes, while the immune system seems to mount a specific immunity with immunoglobulin E (IgE). However, although there is a consensus about what the scientific community overall means by atopy , there remains a never-ending discussion on how to best define this in a consensual definition. For instance, the probably best definition of atopy remains the following: “atopy is a personal and/or family tendency to become sensitized and produce IgE antibodies in response to ordinary exposures to allergens, usually proteins. As a consequence, these individuals can develop typical symptoms of asthma, rhino-conjunctivitis and eczema/dermatitis.” The dilemma of this definition is that most of the scientists would stick to the proof on an IgE-mediated sensitization in a distinct individual to apply the term atopy. However, in the given definition, it seems obvious that the production of IgE is a consequence of this predisposition, and not the origin. This subtle distinction is of particular significance when it comes to consider the very early phase of AD, where a given individual starts to have typical clinical symptoms of the disease but the sensitization against environmental allergens cannot yet be detected because it is expected to appear during the course of the disease. Therefore, the very early phase of AD in infancy (phase 1) is related to an atopic predisposition even if increased total IgE and/or specific IgE cannot yet be demonstrated, at least with the available panel of allergens and technologies.

What about intrinsic versus extrinsic atopic dermatitis?

Among the patients suffering from typical clinical symptoms compatible with the diagnosis of AD, there seems to be a subgroup in which the patients lack increased total IgE or specific IgE to common allergens. Interestingly, the same phenomenon as described for the disease itself with multiple different denominations, is reproduced for this particular subgroup for which different terms have been coined such as intrinsic AD, atopy form dermatitis, or non–IgE-associated dermatitis or nonatopic eczema . As mentioned, normal IgE and/or the lack of detectable specific IgE can be encountered mainly in 2 situations: (i) in infancy or early childhood when the clinical dermatologic symptoms are present, but the sensitization process has not yet led to the generation of increased IgE synthesis. Interestingly, many studies have highlighted the fact that the situation is more frequent in female individuals than in males. Similarly, (ii) in the so-called late onset of the disease, this particular form affects mainly females with a rather mild form of the disease, emerging in the absence of increased total IgE or seemingly detectable specific IgE. There is currently no convincing explanation for the fact that IgE sensitization occurs earlier and in a more pronounced way in males than in females.

However, the existence of a non–IgE-associated form of AD can be strongly questioned. Indeed, the cutoff for the so called ‘normal IgE’ has been fixed at around 100 kU/L. In contrast, the exploration of specific IgE is limited to a distinct more or less large panel of common allergens. Thus, we will always face the typical issue of the limitation of the value of IgE as a reliable biomarker to appreciate the atopic status of a patient and his very individual and personalized sensitization profile. In fact, most physicians have frequently faced the situation of patients with normal total IgE (<100 kU/L) but clear-cut oligosensitization to some relevant allergens such as house dust mite or pollens with significant proportion of specific IgE within this normal total IgE amount. This kind of oligosensitization is most probably of much more clinical relevance for a given individual compared with other patients with very high IgE level (>1000 kU/L) and a wide spectrum of the so-called specific IgE as measured by radioallergosorbent test. Therefore, not only the cutoff of total IgE may seriously be questioned, but also the panel of allergens used in the detection of the individual sensitization profile.

Moreover, we always use the term ‘specific IgE’ in our scientific discourse. This term is used usually because we have a tremendous gap between the sum of the so-called specific IgE amount and the total IgE level in many patients with high overall IgE levels. Clearly, in the 1970s, when the detection of specific IgE and the availability of purified allergen for this detection was rather limited, the panel of possible allergens and the detection of specific IgE was rather limited. With time and new technologies, including the availability of recombinant allergens, the panel of available allergens for exploring the sensitization profile of a given individual has increased dramatically. Thus, owing to technical progress in in vitro diagnostics, the spectrum of possible specific IgE is increasing whereas the spectrum of the so-called non-IgE within the total IgE amount is gradually decreasing. In this regard, a key statement should be considered: There is no “nonspecific IgE”; there is only IgE from which we do not yet know the specificity!

From these considerations, the binary view of AD and the existence of a non-IgE-associated (intrinsic, atopiform, etc) can be seriously questioned. Indeed, a more thorough exploration of the specific IgE particularly for microbial agents or self-proteins in individuals with normal total IgE (according to the current cut-off point) would probably allow to detect some level of sensitization in each individual affected by AD.

Another important aspect that supports this exposed concept is the fact that there is a well-established correlation between the severity of the disease and at least the amount of total IgE. More recently, some transcriptomic analyses of intrinsic forms of AD have shown partly conflicting results. The differences more rely on the expression of other cytokines like Th-22 and Th-17, which may potentially counterbalance the Th-2 dominance in terms of IgE synthesis and, therefore, limit at least to some point the ongoing sensitization mechanisms in these individuals. Similarly, differences in FLG mutations do not seem to fully explain the phenomenon. Our clinical experience also shows that although there may be some patients who show an increase in severity by the time in the early phase of the disease, particularly in childhood, in many instances the degree of severity of a given patient is a rather stable phenomenon, which seems to be an important factor in driving the sensitization phenomenon. The key question of the future will be to identify the mechanisms responsible for driving the severity and to find suitable and related biomarkers with a prognostic or predictive value for these individuals.

Impact of the definition on the diagnostic criteria for atopic dermatitis

Since the first diagnostic criteria from Hanifin and Rajka in the early 1980s, a number of other diagnostic criteria more or less based on the latter, have been proposed and listed on Table 1 . A comparative view of the “must have” in the 3 most used criteria, that is, the Hanifin and Rajka, the UK working party and the criteria from the American Academy of Dermatology ( Table 2 ) shows the different perceptions of the individual diagnostic items with regard to the qualitative major criteria used. The value of qualitative versus quantitative AD criteria is of great importance and has been excellently discussed in details elsewhere. A first short survey performed in 2016 across Europe, the United States, and Asian countries including Japan, Korea, Thailand, and China has shown that the use of diagnostic criteria is very much dependent on the context in which the diagnosis of AD must be ascertained (Bieber, personal communication, 2016). Although in most clinical trials the criteria of Hanifin and Rajka are still considered as the gold standard, the situation is by far different when it comes to the first choice of diagnostic criteria in a routine work. Interestingly, the Diepgen criteria are only used in Europe. The Japanese Dermatological Association criteria are mainly used in Japan, but also to some extend in China. The UK Working Party criteria are mainly used in Europe and in China but not in the United States. In the United States, the criteria of the American Academy of Dermatology are the preferred ones. As expected, some national criteria, such as in Thailand and India, are primarily used in these countries.

Table 1

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